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Human Papillomavirus Type 16 E6 Inactivation of p53 in Normal Human Mammary Epithelial Cells Promotes Tamoxifen-mediated Apoptosis¹

Division of Medical Oncology, Duke University Medical Center, Durham, North Carolina 27710 [V. L. S., E. C. D.]; Division of Hematology and Oncology and the Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210 [K. M.]; School of Medicine, University of Washington, Seattle, Washington 98195 [M. P.]; and Program in Electron Microscopy, Fred Hutchinson Cancer Research, Seattle, Washington 98109 [L. E. C.]

Aberrant p53 expression is frequently observed in mammary epithelial cells obtained from women at high risk for developing breast cancer and is a predictor for the subsequent development of malignancy. Tamoxifen has recently been shown to reduce the incidence of noninvasive breast cancer in high-risk women, but the molecular mechanism of tamoxifen chemoprevention in mammary epithelial tissue that does not overexpress the estrogen receptor is poorly understood. We suppressed p53 expression by retroviral-mediated expression of human papillomavirus type-16 E6 protein (HPV-16 E6) in human mammary epithelial cells (HMECs) to develop an in vitro model of tamoxifen chemoprevention in the context of p53 loss. Early passage p53(-) HMEC-E6-transduced cells treated with 1.0 µM tamoxifen rapidly underwent apoptosis. In contrast, early passage p53(+) HMEC-LXSN vector controls treated with 1.0 µM tamoxifen underwent G₁-G₀-phase arrest but did not undergo apoptosis. p53(-) HMEC-E6 cells rapidly acquired resistance to tamoxifen-mediated apoptosis after 10 passages in culture (in the absence of tamoxifen). Both p53(+) and p53(-) HMECs exhibited a low level of estrogen receptor staining and minimal estrogen binding, characteristic of proliferating normal luminal mammary epithelial cells. Tamoxifen-mediated apoptosis in p53(-) HMEC-E6 cells was not blocked by inhibitors of transcription and protein synthesis. These data suggest that the acute loss of p53 function in HMECs by expression of HPV-16 E6 results in marked sensitivity to tamoxifen-mediated apoptosis but that resistance to apoptosis rapidly develops within 10 passages in vitro. Observations in our model system predict a critical role for the early institution of tamoxifen chemoprevention.

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